The compound N-[2-(diethylamino)ethyl]-5-[-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, also named sunitinib (Formula I) has been shown to act as an inhibitor of protein kinases.

WO 01/60814 generally relates to pyrrole substituted 2-indolinone protein kinase inhibitors and includes sunitinib. In addition salts for the general class of compounds are generally referred to, such as positively charged moieties including quaternary ammonium, salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, malate, maleate, succinate; and negatively charged species. WO 01/60814 is silent as to the preparation of and the nature of specific crystal forms of salts.
In WO 03/016305 it is said that the free base and salts of sunitinib had been screened for properties related to the processing of the salt and the preparation of oral pharmaceutical compositions therefrom, including, for example, crystallinity, toxicity, hygroscopicity, stability, and morphology. Malate salt was chosen from the screening and two crystal forms of sunitinib L-malate, designated as Form I and Form II, were disclosed.
Polymorphism is defined as the ability of a substance to crystallize in more than one crystal lattice arrangement. Polymorphism can influence different aspects of solid state properties of a drug. Different crystal forms of a substance may differ considerably from one another in many respects such as their solubility, hygroscopicity, stability, solubility and/or dissolution rate, crystallinity, crystal habits, bioavailability and formulation handling characteristics.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
Moreover, it would be desirable to provide a process for more selectively preparing a predetermined polymorphic form of sunitinib malate from among different theoretically existing polymorphic forms.
Thus, there is a need in the art for new polymorphic forms of sunitinib malate that have better thermal stability, and offer advantages for preparing reproducible pharmaceutical formulations. Further, there is a need to provide a predetermined polymorphic form in an aimed and reproducible manner, thereby allowing to obtain the desired specific, predetermined form in good purity.
The present invention satisfies this need by providing new crystal form comprising malic acid salt of sunitinib with greater thermodynamic stability, and by providing improved process for repeatedly obtaining a desired specific, predetermined form.